Currently, 800,000 patients receive chemotherapy in the United States each year. Myelosuppression and oral toxicity are common in conventional chemotherapy and are exacerbated by high dose and/or schedule intensification. As chemotherapeutic dosage has been identified as a major predictor of treatment outcome in a variety of cancer treatment programs, overcoming dose limiting toxicity has become a major goal for oncologists. Thus, to allow intensification of chemotherapy, it will be essential to prevent these unwanted side effects.
Studies have shown that oral toxicity is a major problem in the clinic (Guggenheimer et al., 1977; Lockhart et al., 1981; Sonis et al., 1988; and Sonis & Clark, 1991). This toxicity is very common and is often dose or schedule limiting in both standard and high dose chemotherapy. As improvements are made in management of hematopoietic toxicity, oral toxicity is more frequently dose and schedule limiting. For example, many of colon cancer patients receiving 5-fluorouracil (5-FU) suffer from oral mucositis. It has been estimated that 40% of chemotherapy patients develop oral complications (Sonis et al., 1978). For example, 67% of leukemia/lymphoma patients, 75% of patients receiving bone marrow transplants following therapy, and approximately 20% of breast cancer patients, suffer from oral mucositis.
Chemotherapy agents which cause oral mucositis include commonly prescribed agents. Single-agent or combination therapies which result in dose or schedule limiting oral and gastrointestinal (GI) toxicity include, but are not limited to, 5-FU, methotrexate, doxorubicin, Melphalan, and AFM regimen, the CEA regimen and the CAF regimen (Sonis et al., 1990).
Oral mucositis following chemotherapy is a consequence of the high proliferative rate of the normal epithelial cells lining the oral cavity. Chemotherapy-induced mucositis in the oral cavity is largely derived from injury to the basal epithelial cell layer. The epithelial lining of the mouth is generally five cells thick, with the self-renewing stem cell layer located at the base, which itself overlays a fibrous connective tissue matrix. In contrast to skin, most of the epithelium which lines the oral cavity are not highly keratinized, and therefore are able to absorb and elicit a biological response to exogenously added peptide growth factors. The epithelium at the base of the mouth divides most rapidly and is most sensitive to chemotherapy.
The extent of oral mucositis appears dependent on the cycling status of the epithelial cell layer. For example, 90% of pediatric chemotherapy patients (ages 1-20) develop oral mucositis, as compared with 18% of patients over the age of sixty (Sonis et al., 1979). Further, in animal models of oral mucositis, increasing proliferation of the oral epithelium by prior administration of growth factor (e.g. EGF, TGF-.alpha.) markedly increases the severity of oral mucositis.
Mucositis results from epithelial thinning and ulceration resulting in severe pain, weight loss from failure to eat or drink (often requiring parenteral feeding), infection (bacterial, fungal and viral), fever, nausea and diarrhea. Symptoms peak 7 to 10 days following therapy, and gradually recede over the following two weeks. The major complications which accompany mucositis include severe pain, pronounced reduction in food and fluid intake and potentially life-threatening infection due to sepsis. Therefore, method& of preventing oral toxicity enable escalated schedules and doses of a chemotherapy regimen, resulting in improved patient long term survival for many human cancers, notably leukemia, lymphoma, testicular, neuroblastoma and breast cancer.
The ability of growth factors to accelerate healing is well known. Recently, U.S. Pat. No. 5,102,870, issued Apr. 7, 1992 from U.S. Ser. No. 339,463, filed Apr. 14, 1989, described the use of growth factors to aid in the healing of oral mucositis. Such factors are used to accelerate healing of the oral mucositis, administered after exposure to the radiation or chemotherapy. This and related approaches aid in healing subsequent to the exposure, they do not address the high proliferative rate of normal epithelial cells that makes them vulnerable to the antineoplastic agents vide supra. As described above administration of growth factors prior to chemotherapy leads to more severe oral mucositis. Therefore methods of slowing the high proliferative rate of oral epithelial cells could have great potential.